Targeting germline or somatic DNA repair defects (beyond BRCA) in pancreatic cancer with niraparib: A phase II study (NIRA-PANC).
Authors: Anup Kasi, Junqiang Dai, Raed Moh'd Taiseer Al-Rajabi, Joaquina Celebre Baranda, Anwaar Saeed, Prabhakar Chalise, Erin Carroll, Shannon Bradbury, Stephen Hyter, Malgorzata Anna Witek, Venkatadri Beeki, Richard J. McKittrick, Manidhar Reddy Lekkala, Anusha Chidharla, Sean Kumer, Timothy Schmitt, Stephen K. Williamson, Steven Soper, Andrew K. Godwin, Weijing Sun
Journal: Journal of Clinical Oncology (2023)

4156 Background: Targeting a molecular subset of pancreatic cancer (PC) may identify alternatives to perpetual chemotherapy and chemo-resistance/toxicity. Poly (ADP ribose) polymerase inhibitors (PARPi) have shown efficacy in germline BRCA mutation via synthetic lethality. Preclinical evidence suggests PARPi may target DNA repair defects beyond BRCA. We conducted a Niraparib phase II study in PC patients with germline/somatic DNA repair defects. Methods: This is an open-label, phase 2 trial in pts with locally advanced or metastatic PC with germline or somatic mutations , known or tested after consent to pre-screening tumor tissue analysis in DNA repair genes (BRCA1/2, PALB2, ATM, NBN, ATR, BRIP1, IDH1/2, RAD51, RAD51B/C/D, RAD54L, CDK12, BARD1, FAM175A, BAP1, CHEK1/2, GEN1, MRE11A, XRCC2, SHFM1, FANCD2, FANCA, FANCC, FANCG, RPA1, ARID1A), who have progressed on or intolerant of at least one line of therapy, no prior PARPi, with evaluable disease, and ECOG PS 0-1. Eligible pts were treated with Niraparib 300mg or 200mg PO daily for 28 days (1 cycle = 28 days) (200mg dose for baseline weight is &lt; 77 kg or baseline platelet count is &lt; 150,000 µL) until disease progression, unacceptable toxicity, investigator decision, withdrawal of consent, or death. The primary objective was 6-month PFS rate. The secondary objectives were OS, DCR and safety. Pts were evaluable for safety if they had received &gt; 1 dose of Niraparib and for efficacy if they had also received &gt; 1 follow-up imaging study. Results: As of Feb 2023, 36 (13 female, 23 male) pts were enrolled, with a mean age of 62.9 (median 64, IQR 51-73, min 41, max 83, SD 11.25), of whom 27 (8 female, 19 male) were evaluable for efficacy. After a median follow-up of 9.0 months (IQR 6.0-15.1 m), the 6-month PFS rate was 40.7% (11/27 pts; 95% CI 4.7%- 100 %). The median PFS is 4.4 m (CI 2.3 - 6.5 m), and median OS is 9.1 m (7.5 -15.1 m). The disease control rate at 8 weeks was 70.4% (19 of 27 pts; 95% CI 49.8%-86.3%). Of the 27 evaluable pts- BRCA2 mutation was seen in 10 pts, ATM (5), CHEK2 (5), BRCA1 (2), NBN (2), ARID1A (1), FANCA (1), FAM175 A (1), RAD51B (1), IDH1 (1), IDH2 (1). Among 36 pts evaluable for safety, treatment-related adverse events occurred in 75% (27/36), and Grade 3 and grade 4 treatment-related adverse events occurred in 31% (11/36). The most common treatment-related AEs were anemia (25%, 9/36), nausea (22%, 8/36), thrombocytopenia (19%, 7/36), vomiting (19%, 7/36), and fatigue (17%, 6/36). Serious treatment-emergent adverse events were reported in 11% (4/36). There were no treatment-related deaths. Conclusions: In previously treated pts with locally advanced and metastatic PC harboring DNA repair defects, niraparib monotherapy yielded a 6-month PFS rate of 40%, median PFS of 4.4 months, and median OS of 9.1 months. Clinical trial information: NCT03553004 . [Table: see text]